Received for publication October 5, 2007.
Revised November 14, 2007.
Accepted for publication November 14, 2007.

The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans

Abstract

The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran (BIBR 953 ZW, beta-Alanine, N-[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl) were studied in 10 healthy males, who received 200 mg [¹⁴C]-dabigatran etexilate (BIBR 1048 MS, the oral prodrug of dabigatran) or an intravenous infusion of 5 mg [¹⁴C]-dabigatran. Radioactivity was measured in plasma, urine and feces over 1 week. The metabolite pattern was analyzed by high performance liquid chromatography with on-line radioactivity detection, and metabolite structures were elucidated by mass spectrometry. Dabigatran etexilate was rapidly converted to dabigatran, with peak plasma dabigatran concentrations being attained after approximately 1.5 h; the bioavailability of dabigatran after oral administration of dabigatran etexilate was 7.2%. Dabigatran was predominantly excreted in the feces after oral treatment, and in the urine after intravenous treatment. The mean terminal half-life of dabigatran was approximately 8 h. The predominant metabolic reaction was esterase-mediated hydrolysis of dabigatran etexilate to dabigatran. Phase I metabolites accounted for 0.6% of the dose in urine and 5.8% of the dose in feces, following oral administration, and 1.5% and 0.2%, respectively, following intravenous administration. Dabigatran acylglucuronides accounted for 0.4% and 4% of the dose in urine after oral and intravenous dosing, respectively. In vitro experiments confirmed that dabigatran etexilate is metabolized primarily by esterases, and that cytochrome P450 plays no relevant role. These findings suggest that pharmacologically active concentrations of dabigatran are readily achieved after oral administration of dabigatran etexilate, and that the potential for clinically relevant interactions between dabigatran and drugs metabolized by cytochrome P450 is low.

Key words: bioavailability, cytochrome P450, drug disposition, excretion, human pharmacokinetics, mass spectrometry, metabolite identification, oral absorption, pharmacokinetics, structure elucidation